Inflammatory demyelination and axonal damage of the central nervous system (CNS) are hallmarks of the chronic stage of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Current MS medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged CNS tissue; they are thus only effective in the acute, but not the chronic stage of disease. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. This goal could be achieved by using ursolic acid (UA), a natural triterpenoid compound found in plants that are widely present in the human diet and in anti-inflammatory medicinal herbs. UA has been recently found to inhibit several types of inflammatory diseases and to prevent EAE when i.p. injected before disease onset, by inhibiting Th1/Th17 cell differentiation. UA also protects neurons from apoptosis. We, for the first time, show that oral UA effectively suppresses ongoing EAE when treatment is started at both acute and chronic stages of EAE, and promotes remyelination in brain- slice culture. Further, UA treatment significantly elevates expression of nuclear factor IL-3 (NFIL3), a transcription factor that has both immunomodulatory and neuroreparative capacities, and lack of NFIL3 expression largely reduces UA effects. The central hypothesis of this proposal is that UA is a novel oral therapy for chronic MS/EAE thanks to its dual effects of immunomodulation and direct neuroregeneration, through NFIL3-induced mechanisms. Three specific aims are proposed to test this hypothesis. From the academic perspective, we have dedicated Specific Aims 1 and 2 to investigation of the mechanisms of UA/NFIL3 action in immunomodulation and neural repair, respectively. From the therapeutic perspective, we will in Specific Aim 3 test the therapeutic effects of UA on the chronic stage of chronic-progressive (CP) and relapsing- remitting (RR) EAE. In addition, potential side effects and safety issues of long-term oral UA will also be closely monitored. This project, if successful, will provide evidence that UA has great potential as an oral anti- inflammatory and neural repair agent for MS, especially at the chronic stage, for which there is currently no effective therapy.